Mechanisms of Notch Signalling in Colon Cancer Initiating Cells

描述(由申请人提供)：最近的研究表明，结直肠癌起始细胞(CCIC)在结直肠癌(CRC)的肿瘤发生和转移中起着重要作用。在初步研究中，我们从原发癌和转移癌中衍生出多个新的CCIC系。我们发现与常用的CRC细胞系相比，CCIC的Noch信号水平显著升高，并且当Notch被抑制时，CCIC经历了细胞周期停滞和细胞凋亡。这项建议的总体目标是了解结肠癌起始细胞中Noch信号的机制以及Noch在人类结肠癌中的作用。这一目标意义重大，因为确定CCIC的关键药物靶点和生物标记物是改进当前结直肠癌化学预防和化疗的创新方法。因此，我们建议(1)确定CCIC抗凋亡、异种移植形成和自我更新中的关键缺口通路成分；(2)检验非类固醇抗炎药(NSAIDs)抑制结肠癌启动细胞中3-分泌酶活性和缺口信号的假说。 公共卫生相关性：最近的研究表明，结直肠癌起始细胞(CCIC)在结直肠癌(CRC)的发生和转移中起重要作用。在初步研究中，我们从原发癌和转移癌中衍生出多个新的CCIC系。我们发现与常用的CRC细胞系相比，CCIC的Noch信号水平显著升高，并且当Notch被抑制时，CCIC经历了细胞周期停滞和细胞凋亡。这项建议的总体目标是了解结肠癌起始细胞中Noch信号的机制以及Noch在人类结肠癌中的作用。了解CCIC中Noch信号转导的机制，有可能为结直肠癌的化学预防和化疗寻找更有效的药物靶点，并发现直接参与肿瘤发生和转移机制的生物标志物。

DESCRIPTION (provided by applicant): Recent studies have provided evidence that colorectal cancer initiating cells (CCIC) are important in colorectal cancer (CRC) tumorigenesis and metastasis. In Preliminary Studies, we derived multiple new CCIC lines from both primary CRCs and metastases. We show that CCIC have significantly elevated NOTCH signaling levels vs. commonly used CRC cell lines, and that CCIC undergo cell cycle arrest and apoptosis when NOTCH is inhibited. The overall goal of this proposal is to understand the mechanism of NOTCH signaling in colon cancer initiating cells and the role of NOTCH in human colon cancer. This goal is significant because identifying critical drug targets and biomarkers for CCIC is an innovative approach to improve current CRC chemoprevention and chemotherapy. We therefore propose to (1) Identify critical NOTCH pathway components in CCIC anti- apoptosis, xenograft formation and self-renewal and (2) Test the hypothesis that Non-Steroidal Anti- Inflammatory Drugs (NSAIDs) inhibit 3-secretase activity and NOTCH signaling in Colon Cancer Initiating Cells. PUBLIC HEALTH RELEVANCE: Recent studies have provided evidence that colorectal cancer initiating cells (CCIC) are important in colorectal cancer (CRC) tumorigenesis and metastasis. In Preliminary Studies, we derived multiple new CCIC lines from both primary CRCs and metastases. We show that CCIC have significantly elevated NOTCH signaling levels vs. commonly used CRC cell lines, and that CCIC undergo cell cycle arrest and apoptosis when NOTCH is inhibited. The overall goal of this proposal is to understand the mechanism of NOTCH signaling in colon cancer initiating cells and the role of NOTCH in human colon cancer. Understanding the mechanism of NOTCH signaling in CCIC has the potential to identify more effective drug targets for CRC chemoprevention and chemotherapy and identify biomarkers directly involved in the mechanisms of tumorigenesis and metastasis.